Submissions for variant NM_001114753.3(ENG):c.360+5G>A

dbSNP: rs1060501417

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000405	SCV001157199	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2019-02-06	criteria provided, single submitter	clinical testing	The ENG c.360+5G>A variant is reported in the literature in an individual with a clinical diagnosis of HHT (Letteboer 2005). In addition, other changes affecting this +5 position (c.360+4_7delAGTG, c.360+5G>C, c.360+5G>T), are also reported in individuals suspected to have HHT (Gedge 2007, Lux 2013). The c.360+5G>A variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a well conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by abolishing the nearby canonical donor splice site. Based on available information, the c.360+5G>A variant is considered to be likely pathogenic. REFERENCES Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. Lux A et al. HHT diagnosis by Mid-infrared spectroscopy and artificial neural network analysis. Orphanet J Rare Dis. 2013 Jun 27;8:94.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001217648	SCV001389497	pathogenic	Hereditary hemorrhagic telangiectasia	2023-07-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15517393, 32573726; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 3 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein. It affects a nucleotide within the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 810952).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001000405	SCV001441151	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2018-01-01	criteria provided, single submitter	research	PM2+PP3+PP4
Ambry Genetics	RCV002454251	SCV002615040	likely pathogenic	Cardiovascular phenotype	2016-07-15	criteria provided, single submitter	clinical testing	The c.360+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 3 in the ENG gene. This variant has been reported in an individual with a clinical diagnosis of hereditary hemorrhagic telangiectasia (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16). In our clinical cohort, this variant was detected in an individual with epistaxis, telangiectasias, pulmonary ateriovenous malformations, and a family history of hereditary hemorrhagic telangiectasia. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480897	SCV004226822	likely pathogenic	not provided	2022-02-02	criteria provided, single submitter	clinical testing	PP3, PM1, PM2, PS4_moderate